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Investigating the hydrogen-bond acceptor site of the nicotinic pharmacophore model: a computational and experimental study using epibatidine-related molecular probes

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Abstract

The binding mode of nicotinic agonists has been thoroughly investigated in the last decades. It is now accepted that the charged amino group is bound by a cation-π interaction to a conserved tryptophan residue, and that the aromatic moiety is projected into a hydrophobic pocket deeply located inside the binding cleft. A hydrogen bond donor/acceptor, maybe a water molecule solvating this receptor subsite, contributes to further stabilize the nicotinic ligands. The position of this water molecule has been established by several X-ray structures of the acetylcholine-binding protein. In this study, we computationally analyzed the role of this water molecule as a putative hydrogen bond donor/acceptor moiety in the agonist binding site of the three most relevant heteromeric (α4β2, α3β4) and homomeric (α7) neuronal nicotinic acetylcholine receptor (nAChR) subtypes. Our theoretical investigation made use of epibatidine 1 and deschloroepibatidine 2 as molecular probes, and was then extended to their analogues 3 and 4, which were subsequently synthesized and tested at the three target receptor subtypes. Although the pharmacological data for the new ligands 3 and 4 indicated a reduction of the affinity at the studied nAChRs with respect to reference agonists, a variation of the selectivity profile was clearly evidenced.

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Acknowledgments

This research was supported by the Italian MIUR (PRIN 2009-R7WCZS), the CNR Research Project on Aging, the Regione Lombardia Project NUTEC ID 30263049 and the Fondazione Giancarla Vollaro, Milano. We acknowledge the CINECA and the Regione Lombardia award under the LISA initiative, for the availability of high performance computing resources and support. Carlo Matera wishes to thank “Dote Ricerca”: FSE, Regione Lombardia, which co-financed his postdoctoral position.

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Authors and Affiliations

  1. Sezione di Chimica Farmaceutica “Pietro Pratesi”, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133, Milan, Italy

    Clelia Dallanoce, Giovanni Grazioso, Diego Yuri Pomè, Carlo Matera & Marco De Amici

  2. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, CNR, Istituto di Neuroscienze, Università degli Studi di Milano, Via Vanvitelli 32, 20129, Milan, Italy

    Cecilia Gotti

  3. Istituto Neurologico Mediterraneo I.R.C.C.S. Neuromed, Via Atinese 18, 86077, Pozzilli, Isernia, Italy

    Miriam Sciaccaluga & Sergio Fucile

  4. Dipartimento di Fisiologia e Farmacologia, Università di Roma La Sapienza, Piazzale A. Moro 5, 00185, Rome, Italy

    Sergio Fucile

Authors
  1. Clelia Dallanoce
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  2. Giovanni Grazioso
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  3. Diego Yuri Pomè
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  4. Miriam Sciaccaluga
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  6. Cecilia Gotti
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  7. Sergio Fucile
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  8. Marco De Amici
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Corresponding author

Correspondence to Giovanni Grazioso.

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Dallanoce, C., Grazioso, G., Pomè, D.Y. et al. Investigating the hydrogen-bond acceptor site of the nicotinic pharmacophore model: a computational and experimental study using epibatidine-related molecular probes. J Comput Aided Mol Des 27, 975–987 (2013). https://doi.org/10.1007/s10822-013-9694-y

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